There is an increasing need for the provision of active compounds for the treatment of obesity and feeding disorders. In recent years there has been a substantial research effort in finding new pharmacological targets for the treatment of these conditions.
One of the most promising targets discovered are peroxisome proliferator activated receptors (PPAR) which are a superfamily belonging to the nuclear hormone receptors, which are ligand activated transcription factors that play a key role in the regulation of the metabolism of lipids and carbohydrates. In addition, it has been discovered that PPAR's also play a key role in satiety induction and ingestion control and corporal fat modulation, as well as in the treatment and prevention of diabetes and cardiovascular diseases.
Three subtypes of PPAR receptors have been described: PPARalpha, PPARgamma and PPARdelta (Kota, B. P. et al. Pharmacol. Res. 51 (2005): 85). The activation by ligands of the PPARgamma subtype enhances the actions of insulin in man and reduces the levels of circulating glucose in diabetes models of rodents. The PPARgamma receptor expressed in adipose tissue, plays a key function in the regulation of the adipocyte differentiation in vitro. The biology of the PPARdelta subtype is less known, although it seems to play an important role in the control of the hyperglycemia and the hyperlipidaemia (Berger, J. y Moller, D. E. Annu. Rev. Med. 53 (2002): 409; Berger, J. et al. J. Biol. Chem. 274 (1999): 6718-6725).
The activation of PPARalpha subtype by its natural ligands is related to the control of the levels of circulating lipids. Fatty acids of medium and long chain and eicosanoids (Forman, B. M. et al. Proc. Natl. Acad. Sci. U.S.A. 94 (1997): 4312) have been described, which produce a substantial reduction of the plasma triglycerides, a moderate reduction of the cholesterol associated with low density lipoproteins (LDL) and a satiety effect. Hence, the alpha subtype of this receptor family is presented as a very interesting therapeutical target for the treatment of diseases related to metabolic alterations, such as dyslipidemias, cardiovascular illness, diabetes and obesity (Cheng, P. T. et al. Mini. Rev. Med. Chem. 5 (2005): 741; Evans, R. M. et al. Nature Medicine 10 (2004): 361).
The dyslipidemias are disorders in the lipids metabolism characterized by abnormal concentrations of one or more types of lipids (e.g. cholesterol and triglycerides), and/or apolipoproteins (e.g. type A, B, C and E), and/or lipoproteins (e.g. low density lipoproteins (LDL), very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL)). The cholesterol molecule is normally transported bound to LDL lipoproteins. The increase of the levels of this composition is directly related to the risk of coronary disease. A smaller percentage of the cholesterol molecule is transported trough the HDL lipoproteins, whose main function is extracting the cholesterol deposited on the arterial walls and transport it to the liver for being eliminated trough the intestine. It has been described that a high level of HDL-cholesterol is associated with the decrease of the risk of coronary disease. Therefore, in the treating of dyslipidemias, decreasing the LDL-cholesterol levels is as important as increasing the HDL-cholesterol levels (Gordon, T. et al. Am. J. Med. 62 (1977): 707. Stampfer; M. J. et al. N. England J. Med., 325 (1991): 373; Kannel, W. B. et al. Ann. Internal Med. 90 (1979): 85-91). At present, fibrate derivatives, such as clofibrate (WO 02009682), bezafibrate and phenofibrate (WO 02015845) are being clinically used for the control of dyslipidemias by binding to the PPARalpha subtype, thus controlling some transcription factors implicated in some of the processes previously described (Linton, M. F. y Fazio, M. F. Curr. Atherioscler. Rep. 2 (2000): 29).
As well as for the treatment of dyslipidemias, dual agonist agents of PPARalpha/gamma are utilized with a potential use for the treatment of diabetes type 2 (Henke, B. R. J. Med. Chem. 47 (2004): 4118). Different glitazones (benzyl-2,4-thiazolidindione derivatives) have been approved for their use in the treatment of diabetes. Among them isaglitazon (WO 03018010), troglitazon, rosiglitazon and pioglitazon (Hulin, B. et al. Current Pharm. Design. 2 (1996): 85) are included. New molecules in development or in different phases of clinical research are demonstrating a dual activity as activators of the PPARalpha and gamma subtypes, such as KRP-297 (Murakami, K. Biochem. J. 353 (2001): 231), some thiazoles (WO 01021602) and propionic acid derivatives (WO 02069994).
Finally, different research lines are focusing on the development of selective agents of the PPARalpha subtype, such as phenylpropionic acid derivatives (Nombra, M. et al. J. Med. Chem. 46 (2003): 3581) or those of triazole and triazolone LY518674 (Xu, Y. et al. J. Med. Chem. 46 (2003): 5121) as potential treatment of diseases related to disorders of the lipidic profile and corporal fat composition.
US 2004/0176426 describes compounds having the following formula
wherein A2 and A3 can be alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, (heteroaryl)alkyl, aryl(heteroalkyl), or (heteroaryl)heteroalkyl; B3 is selected from -hydrogen, -alkylene-C(O)R3, —C(O)R3, alkylene-C(O)N(R3R4), —C(O)N(R3R4), alkylene-S(O)nN(R3R4), S(O)nN(R3R4) alkylene-N(R3R4), alkylene-OR3, and —C(O)OR3 (wherein R3 and R4 can be hydrogen, alkyl, heteroalkyl, cycloalkyl among others); X is C, S, or N; and p is an integer from 0 to 2.
The compounds described in US 2004/0176426 are useful in modulating the farnesoid X receptor (FXR). According to US 2004/0176426 FXR forms heterodimers with the retinoid X receptor (RXR) in some cell types, modulation of the level of FXR activity in cells has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPARgamma and PPARalpha.
However, from all the possible families of compounds described in US 2004/0176426, no mention is made to acyclic sulfamide derivatives or to their activity in satiety induction and ingestion control, corporal fat modulation and lipidic metabolism regulation or for the treatment or prevention of diabetes and cardiovascular diseases.
U.S. Pat. No. 4,171,223 describes non-diffusible thioether compounds capable of reacting with the oxidation products of a primary aromatic amino colour developer substance to release a diffusible silver halide development inhibitor compound with the following formula

N-dodecyl-sulfamide is disclosed in the same document as an intermediate for the synthesis of the above compounds.
U.S. Pat. No. 4,218,357 describes compounds with the following formula
wherein R is selected from the group consisting of C1 to C30 alkyl, cycloalkyl of 4 to 10 carbon atoms, aryl of 6 to 14 carbon atoms and substituted aryl or C1 to C30 alkoxy, among others; and R1 and R2 are independently selected from hydrogen and the group consisting of C1 to C30 alkyl, cycloalkyl of 4 to 10 carbon atoms, aryl of 6 to 14 carbon atoms and substituted aryl.
The compounds described in U.S. Pat. No. 4,218,357 are platifiers used as additives for polymers. Specifically, U.S. Pat. No. 4,218,357 discloses the following compound
as a suitable plastifier additive.
Although the current agents are giving good results in the treatment of some of the above mentioned diseases, it is still necessary to continue searching alternative compounds with therapeutic potential, better pharmacokinetic properties and reduced toxicity.